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(See the editorial commentary by Von Reyn, on pages 817–9.) The epidemics of tuberculosis and human immunodeficiency virus type 1 (HIV) infection converged with the greatest intensity in sub-Saharan Africa. Both the incidence and the prevalence of tuberculosis increased as the HIV infection epidemic swept through the continent. In Africa today, tuberculosis may affect up to 30% of coinfected persons [1] and is the leading cause of death. Even with effective antituberculosis treatment, case fatality rates for tuberculosis may be as high as 20%, especially in the face of severe immunosuppression [2, 3]. Moreover, tuberculosis may accelerate the clinical course of HIV infection and lead to poor outcomes [4–7]. Newly revised guidelines from the World Health Organization (WHO) recommend the use of antiretroviral therapy for all HIV-seropositive persons with tuberculosis disease, regardless of their CD4+ T-cell count [8]. Recent evidence indicates that antiretroviral therapy should be started early in the course of tuberculosis treatment because it improves survival [9, 10]. Although there is abundant information on the benefit of antiretroviral therapy in HIV-infected tuberculosis patients with advanced immunosuppression [11–13], there are fewer data on the optimal management of tuberculosis among patients with CD4+ T-cell counts of >350 cells/μL. The present study was designed in the early years of the antiretroviral therapy rollout in Africa to determine whether a 6-month course of antiretroviral therapy given concurrently with tuberculosis treatment would improve the clinical, immunologic, and virologic outcomes among patients with CD4+ T-cell counts of >350 cells/μL. The rationale of the study was that a punctuated course of antiretroviral therapy in patients with high CD4+ T-cell counts would suppress viral replication during therapy for tuberculosis, block the effects of immune activation on T cells harboring HIV, slow the pace of HIV disease progression, and improve clinical outcomes. Although treatment interruption is no longer a viable option given recent advances in the field of HIV infection management [14], the present study provides evidence of clinical benefit when starting antiretroviral therapy in tuberculosis patients with preserved immunity.

BACKGROUND: Triple nucleoside reverse transcriptase inhibitor regimens have advantages as first-line antiretroviral therapy (ART), avoiding hepatotoxicity and interactions with anti-tuberculosis therapy, and sparing two drug classes for second-line ART. Concerns exist about virological potency; efficacy has not been assessed in Africa. METHODS: A safety trial comparing nevirapine with abacavir was conducted in two Ugandan Development of Antiretroviral Therapy in Africa (DART) centres: 600 symptomatic antiretroviral-naïve HIV-infected adults with CD4 counts

In the first preventative human immunodeficiency virus (HIV) vaccine study to be carried out in Africa, 40 HIV-seronegative Ugandan volunteers were randomly assigned to receive a canarypox vector containing HIV-1 clade B (env and gag-pro) antigens (ALVAC-HIV; n = 20), control vector containing the rabies virus glycoprotein G gene (n = 10), or saline placebo (n = 10). Cytotoxic T lymphocyte activity against target cells expressing clade A, B, and D antigens was assessed using standard chromium-release and confirmatory interferon-gamma enzyme-linked immunospot (ELISPOT) assays. Neutralizing antibody responses to cell line-adapted strains and primary isolates in all 3 clades were also tested. Twenty percent of vaccine recipients generated detectable cytolytic responses to either Gag or Env, and 45% had vaccine-induced HIV-specific CD8(+) T cell responses, as measured by the ELISPOT assay. In contrast, only 5% of the control group had vaccine-specific responses. Neutralizing antibodies against primary and laboratory-adapted HIV-1 clade B strains were seen in 10% and 15% of vaccine recipients, respectively, but responses against clades A and D were not detected. Although the immunogenicity of this clade B-based vaccine was low, ALVAC-HIV elicited CD8(+) T cell responses with detectable cross-activity against clade A and D antigens in a significant proportion of vaccine recipients.

Summary Background Little is known about how to implement antiretroviral treatment programmes in resource-limited countries. We assessed the UNAIDS/Uganda Ministry of Health HIV Drug Access Initiative—one of the first pilot antiretroviral programmes in Africa—in which patients paid for their medications at negotiated reduced prices. Methods We assessed patients' clinical and laboratory information from August, 1998, to July, 2000, from three of the five accredited treatment centres in Uganda, and tested a subset of specimens for phenotypic drug resistance. Findings 912 patients presented for care at five treatment centres. We assessed the care of 476 patients at three centres, of whom 399 started antiretroviral therapy. 204 (51%) received highly active antiretroviral therapy (HAART), 189 (47%) dual nucleoside reverse transcriptase inhibitors (2NRTI), and six (2%) NRTI monotherapy. Median baseline CD4 cell counts were 73 cells/μL (IQR 15–187); viral load was 193 817 copies/mL (37 013–651 716). The probability of remaining alive and in care was 0·63 (95% CI 0·58–0·67) at 6 months and 0·49 (0·43–0·55) at 1 year. Patients receiving HAART had greater virological responses than those receiving 2NRTI. Cox's proportional hazards models adjusted for viral load and regimen showed that a CD4 cell count of less than 50 cells/μL ( vs 50 cells/μL or more) was strongly associated with death (hazard ratio 2·93 [1·51–5·68], p=0·001). Among 82 patients with a viral load of more than 1000 copies/mL more than 90 days into therapy, phenotypic resistance to NRTIs was found for 47 (57%): 29 of 37 (78%) who never received HAART versus 18 of 45 (40%) who received HAART (p=0·0005). Interpretation This pilot programme successfully expanded access to antiretroviral drugs in Uganda. Identification and treatment of patients earlier in the course of their illness and increased use of HAART could improve probability of survival and decrease drug resistance.

Pleural tuberculosis (TB) was employed as a model to study T cell apoptosis at sites of active Mycobacterium tuberculosis (MTB) infection in human immunodeficiency virus (HIV)-coinfected (HIV/TB) patients and patients infected with TB alone. Apoptosis in blood and in pleural fluid mononuclear cells and cytokine immunoreactivities in plasma and in pleural fluid were evaluated. T cells were expanded at the site of MTB infection, irrespective of HIV status. Apoptosis of CD4 and non-CD4 T cells in the pleural space occurred in both HIV/TB and TB. Interferon (IFN)-gamma levels were increased in pleural fluid, compared with plasma. Spontaneous apoptosis correlated with specific loss of MTB-reactive, IFN-gamma-producing pleural T cells. Immunoreactivities of molecules potentially involved in apoptosis, such as tumor necrosis factor-alpha, Fas-ligand, and Fas, were increased in pleural fluid, compared with plasma. These data suggest that continued exposure of immunoreactive cells to MTB at sites of infection may initiate a vicious cycle in which immune activation and loss of antigen-responsive T cells occur concomitantly, thus favoring persistence of MTB infection.

SUMMARYImmune parameters were compared in four groups of Ugandan subjects: HIV−and HIV+ adult patients with active pulmonary TB (HIV− PTB n = 38; HIV+ PTB n = 28), patients with HIV infection only (n = 26) and PPD+ healthy controls (n = 25). Compared with healthy controls, CD4 and CD8 T cells from patients with HIV and/or PTB expressed more activation markers (HLA-DR, CD38); their CD8 T cells expressed more CD95 (pre-apoptosis) and less CD28 (co-stimulatory receptor). Peripheral blood mononuclear cells (PBMC) of patients with either HIV or PTB were impaired in interferon-gamma (IFN-γ) production upon antigenic stimulation. PTB (with or without HIV) was characterized by monocytosis, granulocytosis, increased transforming growth factor-beta 1 production and PPD-induced apoptosis. In vivo CD4 T cell depletion, in vitro increased spontaneous CD4 T cell apoptosis and defects in IFN-γ responses upon mitogenic stimulation were restricted to HIV+ subjects (with or without PTB). Overlapping and distinctive immune alterations, associated with PTB and HIV, might explain mutual unfavourable influences of both diseases.

The first prophylactic human immunodeficiency virus type 1 (HIV-1) vaccine trial in Africa, with a clade B immunogen, is currently under way in Uganda, in a region where clades A and D are endemic. The use of a B clade vaccine is based on anticipated cross-recognition of endemic strains of HIV-1 in Uganda, but, in fact, little is known about the cytotoxic T lymphocyte (CTL) responses in that region. Seventeen HIV-1-infected volunteers from Kampala, Uganda, were studied to determine the immune responses elicited by natural infection with local HIV-1 strains. Despite the presence of broad cross-clade recognition, the CTL responses to the infecting viral clade were highest in most people. Recognition of nonendemic clade B antigens was similar to that of the coendemic local clade, and, in some instances, cross-recognition of clade B was greater. Nevertheless, the degree of cross-clade cellular responses we observed lends justification to the use of clade B-based immunogens in the current phase 1 vaccine trial in Uganda.

CXCR4, a coreceptor for T cell (T)-tropic HIV-1, is preferentially expressed on naive T cells, whereas CCR5, a coreceptor for macrophage (M)-tropic HIV-1, is preferentially expressed on previously activated memory T cells and the Th1 subset of CD4+ T cells. CCR4 is preferentially expressed on the Th2 subset of CD4+ T cells. A cross-sectional flow cytometry study was conducted to evaluate the expression of CXCR4, CCR5, and CCR4 on the peripheral blood CD4+ T cells from African HIV-1-infected and uninfected Ugandan adults. The plasma viral load in HIV-1-infected individuals was also examined. Upregulation of CCR4 and CCR5 expression but no decrease in CXCR4 expression on CD4+ T cells were obtained in peripheral blood from African adults with progression of the disease. Plasma HIV-1 viremia significantly and inversely correlated with the peripheral CD4+ T cell count but did not correlate with the degree of CCR4 and CCR5 expression on the peripheral CD4+ T cells in HIV-1-infected individuals. Our present data suggest an increase in percentage of activated memory CD4+ T cells in the advanced stage of HIV-1 infection among African adults. There was no evidence of a Th1 to Th2 shift in terms of chemokine receptor expression profile with advancing disease in the peripheral blood of these subjects.

Mycobacterium tuberculosis (MTB)-induced T cell responses are depressed in peripheral blood mononuclear cells of persons with newly diagnosed pulmonary tuberculosis (TB), and levels of interferon (IFN)-gamma remain low even after completion of antituberculous therapy. Loss of MTB-reactive T cells through apoptotic mechanisms could account for this prolonged T cell hyporesponsiveness. T cell apoptosis was studied in TB patients and healthy control subjects. Both spontaneous and MTB-induced apoptosis (in CD4 and non-CD4 T cells) from TB patients was increased when compared with healthy control subjects, whereas coculture with control antigen (candida) had no effect on T cell apoptosis in either group of study subjects. An inverse correlation existed between increased MTB-induced T cell apoptosis and IFN-gamma and interleukin (IL)-2 immunoreactivities. Successful antituberculous chemotherapy resulted in a 50% reduction in both spontaneous and MTB-induced apoptosis, which coincided with 3- and 8-fold increases in levels of MTB-stimulated IL-2 and IFN-gamma, respectively. These data indicate that apoptotic pathways are operant during active MTB infection and may contribute to deletion of MTB-reactive T cells and the immunopathogenesis of this disease.

Despite current efforts to combat HIV/AIDS through behavioural change, ingrained socio-cultural practices such as widow inheritance in south-western Uganda has not changed. Low education, unemployment, dowry, widows' socioeconomic demands and the inheritor's greed for the deceased's wealth, influence widow inheritance. Voluntary counselling and testing is needed for the widows and their inheritors; formal dowry should be removed from marriage and widow inheritance stripped of its sexual component.

Summary Setting: This pilot study was conducted at the Joint Clinical Research Centre (JCRC) in Kampala, Uganda, where tuberculosis (TB) is an epidemic health problem aggravated by the HIV-1 pandemic. Objective: To evaluate the feasibility of a larger phase III trial utilizing rifabutin as a substitute for rifampicin in short-course therapy for pulmonary TB. Design: Single-blind randomized trial in 50 patients with new onset smear- and culture-positive pulmonary tuberculosis and HIV-1 infection. Comparison of daily, intermittently supervised 6-month treatment regimens of rifabutin versus rifampicin, together with isoniazid, ethambutol and pyrazinamide. Results: Rifabutin- and rifampicin-containing regimens had comparable efficiency. However, rifabutintreated patients had significantly more rapid clearance of acid-fast bacilli from sputum at 2 months ( P P Mycobacterium africanum from 49% of the sputum cultures. This is the first report indicating a high prevalence of M. africanum in human TB in Uganda. Conclusion: Short-course antituberculosis regimens containing rifabutin or rifampicin are both safe and efficacious in the treatment of HIV-1 associated tuberculosis. Rifabutin-containing regimens were associated with earlier sputum smear and culture conversion.

1and new resources have become available. 2 Although expense, feasibility, and effective delivery remain formidable barriers, public health and technical agencies have started to re-examine their assumptions and to discuss use of antiretroviral drugs in poorly resourced environments. 3 Data lending support to use of antiretroviral treatment in poorly resourced regions are few. Even in well resourced countries, clinicians still do not have evidencebased answers to simple issues such as: when to start antiretrovirals, how to monitor their therapeutic and toxic effects, and in what sequence to use them. Answers to such issues are greatly needed to speed up delivery of antiretrovirals to the populations most in need of treatment. As a working group convened by the Rockefeller Foundation, we outline an urgent research agenda that attempts to identify gaps in knowledge and to prioritise issues affecting access to treatment for the tens of millions of adults living with HIV/AIDS in poorly resourced regions. Answers to many of these questions will also benefit patients in well resourced regions. We do not address the equally important issues about use of antiretrovirals in infants and children and of prevention of mother-to-child transmission. When should antiretroviral treatment be started? Use of antiretroviral treatment is straightforward in adults with symptomatic HIV-1 disease or CD4+ counts of 200 or less, 4–6 but whether asymptomatic adults with more

Objective: Design: Setting: Results: Conclusions: This study demonstrates that abstinence and use of condoms on their own may not be enough for HIV prevention among PLWHAs who desire children. Additional methods such as use of ART to reduce HIV infectiousness and sperm washing are needed. In the past 12 months 227 (60%) of the PLWHAs were sexually active. Of the sexually active 42 (19%) never used a condom, and 92 (40%) used condoms inconsistently, thus 134 (35%) of PLWHAs engaged in high risk sex. Two hundred and sixty five (70%) said that PLWHAs can have healthy children and 115 (30%) desired more children with 21 (10%) of the women in the reproductive age group reporting a pregnancy and 22 (17%) of the men reporting having caused a pregnancy. Only three (7%) of the pregnancies were unplanned. Desire for more children was a strong independent predictor of engaging in high risk sex (Adjusted Odds Ratio 2.44, 95% CI 1.35-4.42). Joint Clinical Research Centre, Kampala Uganda. Participants: Three hundred and eighty PLWHAs, 50% of whom had initiated antiretro viral therapy (ART). Main outcome measures: PLWHAs answered questions regarding sexual behaviour, number and type of sexual partners, symptoms of sexually transmitted infections, having been pregnant or causing a pregnancy, social demographic characteristics, consumption of alcohol, having biological children, desire for more children and use of condoms. A cross sectional study. To identify sexual behaviour and reproductive health needs of people living with HIV/AIDS (PLWHAs).

BACKGROUND: We sought to investigate renal function in previously untreated symptomatic human immunodeficiency virus (HIV)-infected adults with CD4(+) cell counts of or =60 but or =30 but

Objectives Polymorphisms in the cytochrome P450 (CYP) 2B6 gene have been shown to influence nevirapine plasma concentrations in HIV-infected European Caucasians. Although nevirapine is used extensively in Africa, the influence of CYP2B6 genotype on nevirapine exposure has not been assessed in this population. We aimed to determine the influence of CYP2B6 genotype at position 516 on nevirapine trough concentrations in HIV-infected patients in Kampala, Uganda. Additional polymorphisms in the CYP and multidrug resistance protein-1 (MDR-1) genes were also assessed for their impact on nevirapine concentrations. Methods The following genotypes were determined in all subjects using polymerase chain reaction–restriction fragment length polymorphism: CYP2B6 G516T, MDR-1 C3435T and G2677T, CYP3A4*1B and CYP3A5*3. Nevirapine plasma concentrations were determined using high-performance liquid chromatography in 23 HIV-infected patients who were generally healthy and had been taking nevirapine 200 mg twice daily for at least 14 days. Analysis of variance with post hoc testing was used to compare nevirapine concentrations among CYP2B6 genotype groups. Results The median nevirapine trough concentration in individuals homozygous for the variant allele (TT) was 7607 ng/mL vs 4181 and 5559 ng/mL for GG and GT individuals, respectively (GG vs TT median ratio=1.82; P=0.011). The mean ratio for TT vs GG individuals (95% confidence interval) was 1.51 (1.18, 1.84). No associations were observed between the other polymorphisms studied and nevirapine concentrations. Conclusions CYP2B6 G516T significantly influenced nevirapine trough concentrations in HIV-infected patients in Uganda. Additional studies in larger patient populations are necessary to further define the potential clinical impact of these preliminary findings.

OBJECTIVE: To measure nevirapine elimination in African adults undertaking a structured treatment interruption (STI) in the DART trial. DESIGN: Cohort (16 women, 5 men; median weight 61 kg) within a randomized trial of management strategies. METHODS: Plasma nevirapine was measured by validated high performance liquid chromatography at 0,1,2,3 and 4 weeks after stopping the drug in a subset of patients undertaking an STI. All patients continued lamivudine plus zidovudine/stavudine for a further 7 days. RESULTS: Two patients with no or low plasma nevirapine concentration at baseline were excluded. Geometric mean plasma concentration when nevirapine was stopped in the remaining 19 patients was 6421 ng/ml (range, 3724-9473). Nevirapine was detected in 15/18 (83%) patients at 1 week, and 5/19 (26%) patients at 2 weeks but was not found any samples collected after 2 weeks. Only one patient had > 100 ng/ml (limit of quantification) at 2 weeks (415 ng/ml, female). The median times to reach thresholds of 200, 100 and 20 ng/ml (limit of detection) were estimated to be 7.6 [interquartile range (IQR), 7.0-10.1], 9.3 (IQR, 8.7-13.0) and 13.2 (IQR, 12.3-18.4) days, respectively, with 3/19 (16%) and 14/19 (74%) estimated to have reached < 20 ng/ml by 7 and 14 days, respectively. CONCLUSION: Although elimination of nevirapine was faster than previously published after a single dose, the data suggest that an additional staggered period of 7-10 days with dual nucleotide reverse transcriptase inhibitor cover is necessary for African patients discontinuing nevirapine.

No Abstract. Malawi Medical Journal Vol. 17(3) 2005: 100-101

During the past year, a group has argued that unsafe injections are a major if not the main mode of HIV-1 transmission in sub-Saharan Africa. We review the main arguments used to question the epidemiological interpretations on the lead role of unsafe sex in HIV-1 transmission, and conclude there is no compelling evidence that unsafe injections are a predominant mode of HIV-1 transmission in sub-Saharan Africa. Conversely, though there is a clear need to eliminate all unsafe injections, epidemiological evidence indicates that sexual transmission continues to be by far the major mode of spread of HIV-1 in the region. Increased efforts are needed to reduce sexual transmission of HIV-1.